Volasertib is an experimental polo-like kinase (Plk) inhibitor researched and developed by Boehringer Ingelheim, which was awarded breakthrough therapy and orphan drug by FDA and FDA in September 2013 and April 2014, respectively. It is used for the treatment of patients with acute myeloid leukemia (AML) aged 65 years and older who are not eligible for intensive induction chemotherapy. Since this drug is not officially launched in China, it has no standard Chinese name. Volasertib is designed to inhibit the activity of regulatory cell mitogenase Plk1, which can prolong the time of cell cycle arrest and lead to apoptosis.
The chemical name of volasertib (Volasertib, I) is N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-isopropyl-6-oxo-2-pteridinyl]amino]-3-methoxybenzamide.

The world patents WO2004/076454, WO2006/018220, WO2007/090844 and WO2009/019205 researched by Boehringer Ingelheim disclosed the preparation method of volasertib and its analogs. Although the preparation method of intermediate is different, the target product is produced by condensation reaction of the intermediate 2-chloro-7-ethyl-7,8-dihydro-5-methyl-8-isopropyl-(7R)-6(5H)-pteridinone(A) and N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-amino-3-methoxybenzamide (B) under acidic conditions.

The above literatures also disclosed the route for preparing intermediate (A):

The intermediate (B) is prepared in two ways: the first one, the intermediate (B) is obtained from the starting material 1,4-cyclohexylamine alcohol after amidation, oxidation, condensation reduction and nitro reduction.

The second one, the intermediate (B) is obtained from the starting material N-cyclohexylmethylpiperazine after condensation reduction, hydrolysis and salification, amidation and nitro reduction.

By investigating the synthesis routes of intermediates (A), (B) and volasertib, the molecular structures of intermediates (A), (B) and volasertib contain many amino functional groups, when condensation, amidation and reduction reactions occur, the competitive side effects may happen in primary amine on cyclohexylamine, secondary amine on piperidine ring and primary amine on benzene ring, which will increase the difficulty of purification and reduce the total yield. Therefore, to seek a kind of synthesis route and preparation method of volasertib and intermediate thereof composed of classical unit reactions that can reduce side effects is of great practical significance for the industrialization of volasertib.